BACKGROUND Main biliary cirrhosis is usually a chronic granulomatous cholangitis, characteristically

BACKGROUND Main biliary cirrhosis is usually a chronic granulomatous cholangitis, characteristically associated with antimitochondrial antibodies. the strongest association (P = 1.7810?19; odds ratio for patients vs. controls, 1.75). Main biliary cirrhosis was also significantly and reproducibly associated with two SNPs at the locus (encoding interleukin-12), rs6441286 (P = 2.4210?14; odds ratio, 1.54) and rs574808 (P = 1.8810?13; odds ratio, 1.54), and one SNP at the locus (encoding interleukin-12 receptor 2), rs3790567 (P = 2.7610?11; odds ratio, 1.51). paederosidic acid methyl ester supplier Fine-mapping analysis showed that a five-allele haplotype in the 3 flank of was significantly associated with main biliary cirrhosis (P = 1.1510?34). We found a modest genomewide association (P<5.010?5) with the risk of disease for SNPs at the locus (encoding transmission transducer and activator of transcription 4) and the locus (encoding cytotoxic T-lymphocyteCassociated protein 4) and 10 other loci. CONCLUSIONS Our data show significant associations between main biliary cirrhosis and common genetic variants at the HLA class II, loci and suggest that the interleukin-12 immunoregulatory signaling axis is relevant to the pathophysiology of main biliary cirrhosis. paederosidic acid methyl ester supplier ( number, “type”:”clinical-trial”,”attrs”:”text”:”NCT00242125″,”term_id”:”NCT00242125″NCT00242125.) Main biliary cirrhosis is the most common autoimmune liver disease, affecting up to 1 1 in 1000 women over 40 years of age.1 Treatment for this chronic cholestatic condition remains empirical.2 The granulomatous destruction of interlobular bile ducts that characterizes main biliary cirrhosis is almost always associated with antimitochondrial antibodies specific for the E2 subunit of the pyruvate dehydrogenase complex.3 The hepatic accumulation of autoreactive T lymphocytes in patients with main biliary cirrhosis, as well as data from animal models of autoimmune cholangitis, implicate T lymphocytes CD4+ T helper lymphocytes in particular in the pathogenesis of main biliary cirrhosis.4C6 A genetic predisposition for primary FLJ39827 biliary cirrhosis has been revealed by analysis of both aggregation data from families and concordance data from twins. The rate of concordance among monozygotic twins is usually 60%,7 with the sibling relative risk estimated as 10.5.8 The coexistence of other autoimmune diseases in patients and the increased prevalence of such diseases in their families is also consistent with a genetic influence.9,10 Among the genes analyzed as susceptibility candidates, only has consistently been associated with primary biliary cirrhosis. confers an paederosidic acid methyl ester supplier increased risk of main biliary cirrhosis in whites, with an odds ratio of 2.4 to 3.3. In addition, the derived populace attributable portion for ranges from 2.8 to 8.8%11,12 (for the derivation, see the Supplementary Appendix, available with the full text of this article at Main biliary cirrhosis has also been associated in some, but not all, studies with variants in (the gene encoding cytotoxic T-lymphocyte-associated protein 4).13C15 To explore the genetic basis of primary biliary cirrhosis, we conducted genomewide association screening of subjects from North America. METHODS PATIENTS AND CONTROLS We used a two-stage design to analyze data from 2072 white subjects (536 patients and 1536 controls) from North America (Fig. 1). Stage 1 consisted paederosidic acid methyl ester supplier of a genomewide association survey of patients with main biliary cirrhosis and controls from Canada, with additional historical controls from the United States. We carried out replication analyses (stage 2) including patients and controls from the United States (stage 2a) and additional patients and controls from Canada (stage 2b), as well as fine-mapping studies of all Canadian subjects from your genomewide association screening (stage 1) and replication analysis (stage 2b). We obtained written informed consent from all subjects, and the study was approved by a local institutional ethics committee at each center. Physique 1 Quality Control and Study Design All patients fulfilled the criteria of the American Association for the Study of Liver Diseases for main biliary cirrhosis,16 and all patients and controls were whites of European origin (as determined by self-report and, for patients.